Beneficial Effects Of Saffron (Crocus Sativus L.) In Ocular Diseases
Crocus sativus L. (saffron) belongs to the Crocoideae, the subfamily of the family of Iridaceae (rich in endemic species), and has the highest economic value. Saffron, the most expensive spice in the world, is obtained by manual collection, drying, and then powdering of 2.5to 3.2-cm-long dark orange stigmas of flowers (Fig. 13.1). Approximately 160 kg of saffron flowers are required to obtain 1 kg of dry stigma. The difficulty of cultivation is the main reason for its expansiveness. Nowadays, saffron is cultivated in European countries, Turkey, Greece, Israel, Pakistan, India, Iran, Egypt, Azerbaijan, China, Japan, and Australia (Rios et al., 1996; Shahi et al., 2016).
The name saffron comes from Arabic and means yellow due to the color carotenoid constituents. Anatolia and the Eastern Mediterranean region are the homelands of according, and some reports state that saffron was brought to Anatolia by the Turks during their migration from Central Asia. Homeros and Hippocrates noted that saffron had been cultivated in the Kashmir region of Iran and India throughout the ages (Javadi et al., 2013). The Mongols introduced saffron to China, the Arabs to Spain, and the Crusaders to Western Europe. Ancient Greek, Roman, and Egyptian civilizations used saffron for painting, perfume, medicine, and cooking. There are records indicating Cleopatra's use of a saffron perfume. It has been use as an aromatic sweetener, perfume, dye, medicine, and even an aphrodisiac in the Middle East for 4000 years. Saffron has valued the same as gold (Giaccio, 2004).
Saffron, a valuable drug, is also of great importance in medicine. Much data exist about the saffron benefits on various diseases in the scientific literature. Modern studies have confirmed the traditional use of saffron, and has taken its place in modern medicine. Saffron has been used in the treatment of depression, nervous system diseases, heart diseases, endocrine system diseases, and immunological diseases and has also been used safely in the treatment of ocular diseases in recent years (Mousavi et al., 2011). Ocular disorders, especially mild-to-moderate glaucoma, and retinal maculopathy, are treated quickly with saffron. For this purpose, many preparations, including saffron extract containing crocin and crocetin as active ingredients, are used in treatment (Rios et al., 1996; Broadhead et al., 2016).
This review will give details on the use of saffron in ocular diseases, its effective compounds, and in vivo and clinical studies. Especially glaucoma and age-related retinal maculopathy diseases will be covered.
Saffron contains more than 150 volatile, flavoring, and phenolic compounds. These compounds are generally in the form of glycosides with different sugar molecules. Apart from them, fatty acids (palmitic, oleic, linoleic acids, etc.), vitamins (riboflavin and thiamine), and flavonoids (kaempferol, delphinidin, quercetin, derivatives, etc.) were also detected in the saffron (Rios et al., 1996; Shahi et al., 2016).
Among the secondary metabolites of saffron, the most important are the colored compound crocin (C44H64O24), bitter-tasting compound picrocrocin (C16H26O7), and fragrant compound safranal (C10H14O) (Fig. 13.2) (Bagur et al., 2018).
FIG. 13.1 Structure of different parts of saffron plant.
(Adapted from Shahi, T., Assadpour, E., Jafari, S.M., 2016. Main chemical compounds and pharmacological activities of stigmas and tepals of ‘red gold’; saffron. Trends Food Sci. Technol. 58, 69e78.)
Crocin, which constitutes more than 10% of the dry saffron mass, has been used as a chemotherapeutic agent according to the recent studies due to its water solubility and inhibitory effect on the growth of cells. Crocin significantly inhibited breast cancer cells, pancreatic cancer cells, and human rhabdomyosarcoma cells. Picrocrocin, derived from zeaxanthin, which is carotenoid by oxidative degradation. Picrocrocin ratio is approximately 4% within the stigmas of dry saffron. Safranal which is the volatile ingredient of saffron, found in 70% in dry mass, is derived from picrocrocin during drying and storage periods by hydrolysis (Fig. 13.2) (Shahi et al., 2016; Bagur et al., 2018).
The stability of saffron is very low and sensitive to pH changes, degraded by light and many oxidants. Therefore, the storage conditions of saffron are very important and should be checked (Bagur et al., 2018).
The carotenoids within the plants are synthesized by chloroplasts and chromoplasts. Saffron contains hydrophilic and lipophilic carotenoids that are most active compounds for many diseases and ocular diseases as well. C-40 containing zeaxanthin, a-carotene, and bcarotene; lycopene; and other carotenoids are known as lipophilic carotenoids of saffron. Hydrophilic carotenoids are crocins (C-20) which are found in saffron in 6%e16% ratio. The solubility of crocins within saffron depends on their sugars. Generally, ester forms of crocetin as monoglycosyl or diglycosyl polyene series were isolated from aqueous fraction of saffron (Shahi et al., 2016; Bagur et al., 2018).
Crocins have deep red color and give their color to the watereasilyandquickly,andthispropertyisusedforidentification and quality control of saffron.
Because of these color properties, the saffron is used in food industries as a natural dye. After oxidative degradation of zeaxanthine, which is C-40 carotenoid, C-10-containing picrocrocin, hydroxysafranal, safranal, and C-20 containing crocetin, crocin are obtained (Fig. 13.2). Owing to changing of pH values within the media, dry saffron is easily oxidized and chemically breaks down by lights and other oxidants (Shahi et al., 2016; Bagur et al., 2018).
Many of the biological effects of saffron are due to the carotenoid compounds it contains. These effects are due to the strong antioxidant activity of carotenoids. Radicals that occur during metabolic reactions are responsible for the oxidation events in our body. Oxidative damage to cells also causes many diseases to occur in organs. The effects of saffron’s carotenoid extract against oxidation are due to (1) interaction with enzymes and (2) ROS direct suppression. In both mechanisms, crocetin was effective and the effect of safranal was shown to be weaker (Bolhassani et al., 2014; Bagur et al. (2018).
Thegroupofactivecompoundsthatareeffectiveinthe treatment of ophthalmological diseases especially for glaucoma and age-related macular degeneration (AMD) arecrocinswhicharewater-solublecarotenoids.Theactivities of crocins for glaucoma and AMD treatment were evaluated in in vitro, in vivo, and clinical studies (Falsini et al., 2010; Bisti et al., 2014; Bagur et al., 2018).
Glaucoma, also known as eye pressure, is an eye disease that results from increased intraocular pressure, resulting in blindness when untreated. Inside the eye, there is a fluid circulating in the front to feed the tissues. This liquid is produced in the eye. In some eyes, this fluid cannot be ejected because of obstruction in the canals and elevated intraocular pressure. This causes damage in the optic nerve (Fig. 13.3) (Weinreb and Khaw, 2004).
Glaucoma, at the beginning, may go unnoticed. It progresses slowly over the years and wreaks havoc. The vision decreases gradually, and when the complaints begin, permanent damage to the visual field is located. In case of acute glaucoma crisis, the eye pressure increases suddenly. The eye also has symptoms.
FIG. 13.2 Main active components of saffron stigma.
FIG. 13.3 Glaucoma formation. (Adapted from https://iristech.co/glaucoma-signs-and-symptoms/, April 2019.
such as redness, pain, blurred vision, and seeing colored rings around lights, in addition to nausea and vomiting. Diagnosis can be made earlier in such patients (Foster et al., 2002; Weinreb and Khaw, 2004).
The purpose of glaucoma treatment is to improve the visual quality of patients. Glaucoma treatment may be implemented by drugs, laser treatment, and surgical treatment. Treatment usually starts with medication; laser or surgical treatment is applied if the damage persists. Appropriate treatment is applied depending on the patient’s condition. Early or late diagnosis, the patient’s age, and whether or not to use drugs properly are important factors. Treatment cannot bring back the old vision but only prevents more vision loss. Selective laser trabeculoplasty (SLT) is an alternative treatment option for glaucoma. It provides a supportive solution when the treatment is not enough in patients receiving medication. It can only be applied to open-angle glaucoma. SLT, which is very effective in correctly selected patients, is a simple treatment method of 3e4 min with no side effects and no harm. It can reduce eye pressure by 20% e30%. The effectiveness of the treatment, which can be administered every 6 months, continues between 6 months and 2 years (Dietlein et al., 2009).
Age-Related Macular Degeneration AMD is a macula (Macula lutea, center of the retina) disease. Macula lutea contains the lutein and zeaxanthin as photoreceptors that are responsible for yellow colorization. These xanthophyll isomers and their action mechanisms were discovered in 1980s. In 1866, the absorption of blue light within the same receptors was described, and then the similar absorption spectra with carotenoids were shown within the macula in 1945 (Beatty et al., 1999; Gehrs et al., 2006).
Generally, increasing of oxidation in the macula AMD occurs, and antioxidant pigments found in the macula are known as protective agents. Decreasing the level of macular pigments causes macular degeneration. In the treatment of macular degeneration, carotenoidcontaining supplements are used (Beatty et al., 1999). AMD is the main reason for blindness in over 65 elderly patients. The scientific literature contains various results according to the countries, age groups, and etc (Bird et al., 1995; Gehrs et al., 2006).
Two different types of AMD diseases are known: dry AMD (atrophic type) and wet AMD (neovascular type). Dry type of AMD is the main reason for more than 20% of the blindness in patients (Gehrs et al., 2006)
1. Dry-type AMD: It is a common form of the disease,which results in slow but progressive visual impairment. This disease, which can progress without notice, constitutes approximately 85%e90% of AMD. Dry type is known as chronic AMD and generally some visual impairment and progresses to severe blind develops (Fig. 13.4) (Ambati and Fowler, 2012).
2. Wet-type AMD: A more serious form of diseasewhich progresses rapidly. This disease is the leading cause of vision loss in older ages and occurs in approximately 10%e15% of AMD patients. Agetype AMD is caused by abnormal development of blood vessels at the back of the eye. These blood vessels can cause blood and fluid leakage, causing loss of your central vision. Age type intensive care
FIG. 13.4 Dry and wet macular degeneration. (Adapted from https://www.medicalmarijuana.com/, April 2019.)
unit can affect your ability to see both near and far as you look at a photo or reading the number of the bus (Fig. 13.4) (Ambati and Fowler, 2012).
The macula covers a very small area called the yellow spot in the middle of the retina layer and responsible for sharp vision (Fig. 13.4). Our vision is weaker in the center of the macula toward sharper edges. Macular degeneration is the result of damage to this yellow point (Beatty et al., 1999; Gehrs et al., 2006).
Retinal areas outside the macula are protected from environmental lights. Therefore, macular degeneration does not lead to complete blindness, but as in Fig. 13.1, it may make the close study and reading impossible without various optical auxiliary devices. The main risk factor for the development of degeneration within the macula is age. It is a retinal disease that causes serious vision loss, especially in the 50year-old population in developed countries. It is the known cause of visual loss in western countries in people older than 65 years. Severe vision loss increases with age (Gehrs et al., 2006).
What are the risk factors for macular degeneration?
• Age: Age is the most important risk factor for macular degeneration. AMD is observed in one in three adults older than 75 years.
• Smoking: Cigarette smoking is one of the factors that increase the risk of developing the AMD. The retina produces high levels of oxygen consumption. Each factor that affects the access of the oxygen to the retina has a negative effect on vision.
• Genetic factors: People with a family of yellow dot diseases have a higher risk of developing this disease.
• Gender: Women are more likely to have yellow spot disease. However, since the life span of women is longer, this can be explained by the fact that women have more time to develop the disease.
• Long lifetime sun exposure: Ultraviolet rays directly damage the retinal tissue and lead to the accumulation of harmful products in the retina.
• Dietary and/or low nutritional value, antioxidantfree diet: It is determined that the rate of macular degeneration is higher in individuals with high nutritional value, low nutritional value, and low antioxidant diet.
• Inactivity: People who do not exercise regularly are more likely to be affected by AMD. Owing to inactivity in dry macular degeneration, failure of the retina to obtain adequate oxygen causes cell death in the macula. Exercises to improve cardiovascular health have a positive effect on the development of macular degeneration (Ambati and Fowler, 2012).
Treatment of AMD
Dry-type AMD cannot be treated with conventional therapies, and only neovascularization therapy, which is an emerging type of treatment is possible (Nowak, 2006) In addition, antioxidant supplement treatment plays a role in delaying of progression in 20%e25% ratio (Friedman et al., 2004; Beatty et al., 1999; Nowak, 2006).
General treatment methods applied for treatment of wet-type AMD are as follows (Nowak, 2006): 1. Photodynamic therapy
2. Thermal laser photocoagulation
3. Transpupillary thermotherapy
4. Antiangiogenic agents
a. Pegaptanib sodium (Macugen)
b. Bevacizumab (Avastin)
c. Ranibizumab (rhuFab V2; Lucentis)
d. Anecortave acetate (Retaane)
e. Triamcinolone acetonide
f. Squalamine lactate (Evizon)
g. Sirna-027 (small interfering RNA, siRNA)
h. VEGF-Trap (VEGF-TrapR1R2; soluble decoy receptor)
i. Angiostatin, endostatin, and PEDF (Pigmentepithelium-derived factor)
In addition, stem cell transplantation has been tried for the treatment of AMD in recent years. Phase I and II studies of some pharmaceutical industries with the stem cells are ongoing. These studies aim to treat especially dry-type macular degeneration using human embryogenic stem cells.
In addition, antioxidant supplementation is also applied for the treatment of AMD as an additional therapy. The use of ascorbic acid, a-tocopherol, glutathione, zinc, and macular carotenoids (lutein and zeaxanthin) plays a both preventive and treatment role against the AMD. Especially, macular carotenoids are well-known and important agents for macular degeneration (Nowak, 2006).
Saffron has strong antioxidant properties because of its polar carotenoids. These polar carotenoids are known as crocin and crocetin and are particularly effective in the treatment of ocular diseases. They protect retinal cells from oxidation and help them to perform their functions when used in the treatment of age-related maculopathy (Broadhead et al., 2015; Heitmar et al., 2019).
Many plant products produced for this purpose contain extracts carrying these polar carotenoids. In the scientific studies conducted in this field, extracts containing carotenoids were used. In vitro, in vivo, and clinical trials have been confirmed to be particularly effective in the treatment of AMD and glaucoma of saffron carotenoids. As a result of the treatment with extracts administered at daily doses of 20e50 mg for 3 months, clinical studies showed statistically significant improvement compared with the control group (Heitmar et al., 2019).
An in vitro assay with pure crocin inhibited damage to the photoreceptors because of concentration in the primary retina cell culture (EC50: 30 mM). In an in vivo study with crocin derivatives isolated from saffron, it was noted that the blood flow in the eye was accelerated and crocin derivatives caused increased vascular enlargement and increased oxygenation (Alavizadeh and Hosseinzadeh, 2014; Xuan et al., 1999).
Clinical Trials for Ocular Diseases with Saffron
Clinical studies with saffron or its extracts were published on three different ocular diseases such as diabetic maculopathy, age-related maculopathy, and glaucoma. Saffron and its active compound crocin have shown significant activities in the clinical trials using the antidiabetic, antiapoptotic, antioxidant, antiinflammatory, antihypertensive, antiatherogenic, and neuroprotective mechanismsintheoculardiseases(Heitmar et al., 2019).
Diabetic macular edema is a main problem especially for patients with type 2 diabetes. These patients were treated with carotenoid fraction of saffron which contains crocin. Crocin is used for preventive or therapeutic purposes for patients with diabetic macular edema. Because of these properties of crocin, many pharmaceutical products contain crocin as an active constituent for maculopathy in the market. Some clinical studies were performed with ready-to-use pharmaceutical preparation to reduce the inflammation in the retinal tissue (Heitmar et al., 2019).
Sepahi et al. (2018) tried 5-mg or 15-mg crocin supplements per day for 3 months in the test group with diabetic macular edema. During the study, HbA1c, fasting blood sugar levels, central macular thickness, and best-corrected visual acuity were measured in every month. After 3 months of application, differences between 15 mg of crocin and placebo for fasting blood sugar level were 18, and for HbA1c, it was 0.76. In the same study, ophthalmic examinations such as central macular thickness and best-corrected visual acuity were also measured, and statistically significant results were found for the 15-mg crocin group. It was concluded that the 15-mg crocin administration per day for patients with diabetic maculopathy improved all symptoms.
In another clinical study, mild and moderate retinal maculopathy was treated with saffron supplement orally. Up to 50-year-old patients with mild and moderate retinal maculopathy were administered orally 20 mg of saffron supplement per day for 3 months. Statistically significant differences were obtained for bestcorrected visual acuity and multifocal electroretinogram response density and latency between test and placebo groups after 3 months. In this study, some other safety properties were also measured, and no adverse and side effects were found at the end (Broadhead et al., 2019).
P2X7 receptors that are responsible for the health of retina occur in our nervous system and retinal inner and outer cells as well. According to literature information, the age-related retinal maculopathy which is the neurodegenerative ocular disease is related to P2X7 receptors. In an in vitro study (Corso, 2016), saffron was tested on mouse primary retinal cells and mouse retinal photoreceptor-derived 661W cells, which were highconcentration ATP-stressed. Saffron increased the viability of both cells and reduced the intracellular calcium level. Owing to the in vitro results, the treatment effects of saffron in the neurodegenerative disease were shown using mouse retinal cell cultures and corrected the relation between P2X7 receptors and agerelated maculopathy (Corso, 2016).
Saffron extract was evaluated for dry-type age-related retinal maculopathy clinically, and the patients took saffron as 50 mg of extract in a gelatin capsule with 250 mg of starch for a period of 3 months. After the treatment period, different ophthalmological parameters such as contrast sensitivity, retinal thickness, and visual acuity were evaluated. Contrast sensitivity and visual acuity were improved significantly, whereas retinal thickness did not change (Riazi et al., 2017).
The oxidative damage plays a role in glaucoma, which is characterized by intraocular hypertension. In a clinical study, the patients with glaucoma were administered 30 mg/day of aqueous saffron extract orally during 1month period. The intraocular pressures of both test and control groups were measured, and statistically significant results showing a decrease were obtained from test group. The pressure of control group was changed from 12.9 3.7 to 10.6 3.0 by water extract of saffron in 3 weeks (Bonyadi et al., 2014).
Saffron was evaluated in another clinical trial against AMD in 20-mg/day dose during 3 months. In this study, 25 patients were used in both groups as test and placebo, and their focal electroretinograms and other clinical scores were recorded as baseline and end point. The focal electroretinograms of test group were significantly increased by saffron in 3 months. They indicated that theresponsible compoundswerecarotenoids in thetreatment of AMD because of their antioxidant properties (Falsini et al., 2010).
As a result of clinical studies performed with the extracts of carotenoids of saffron, it has been shown that statistically significant results are obtained in both glaucoma and AMD. In these studies, patients older than 50 years were selected, and 20e50 mg of daily dose was administered orally for 3 months. As a result of the studies, different data were evaluated, and statistically significant results were obtained. According to these studies, significant results were obtained especially in the treatment of diabetes and glaucoma and maculopathy diseases that are related to diabetes and age. In addition, the levels of various biochemical substances related to diabetes in patients with diabetes also reached normal limits.
The activity of saffron depends on the crocin and crocetin, which are saffron carotenoids formed from zeaxanthin. Saffron carotenoids are the responsible components because of their antioxidant properties for the ocular diseases such as glaucoma and AMD.
At the end, saffron can be recommended for both preventive and therapeutic purposes, especially in the treatment of diabetic glaucoma and AMD.
Original Paper: Koşar M, Başer KH. Beneficial effects of saffron (Crocus sativus L.) in ocular diseases. InSaffron 2020 Jan 1 (pp. 155-161). Academic Press.
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Assistant Professor of Environmental Health Engineering in Gonabad University of Medical Sciences, Razavi Khorasan, Iran